Bottom Line:
These effects were exquisitely TEC-subset specific.Nevertheless, cTECs were more abundant in males than females.Accumulation of cTECs in males correlated with differential expression of genes regulating cell survival in cTECs and cell differentiation in mTECs.

ABSTRACTThe goal of our study was to evaluate at the systems-level, the effect of sex hormones on thymic epithelial cells (TECs). To this end, we sequenced the transcriptome of cortical and medullary TECs (cTECs and mTECs) from three groups of 6 month-old mice: males, females and males castrated at four weeks of age. In parallel, we analyzed variations in the size of TEC subsets in those three groups between 1 and 12 months of age. We report that sex hormones have pervasive effects on the transcriptome of TECs. These effects were exquisitely TEC-subset specific. Sexual dimorphism was particularly conspicuous in cTECs. Male cTECs displayed low proliferation rates that correlated with low expression of Foxn1 and its main targets. Furthermore, male cTECs expressed relatively low levels of genes instrumental in thymocyte expansion (e.g., Dll4) and positive selection (Psmb11 and Ctsl). Nevertheless, cTECs were more abundant in males than females. Accumulation of cTECs in males correlated with differential expression of genes regulating cell survival in cTECs and cell differentiation in mTECs. The sexual dimorphism of TECs highlighted here may be mechanistically linked to the well-recognized sex differences in susceptibility to infections and autoimmune diseases.

f4: Relative expression of genes contributing to the inhibition of cell death and cell differentiation in male TECs.(a) Relative expression of genes that affect cell death in cTECs. (b) Relative expression of genes that affect cell differentiation in mTECs. Relative gene expression is depicted as a Z-score, calculated separately for cTECs and mTECs. Red corresponds to higher expression, whereas blue corresponds to lower expression.

Mentions:
We then sought to gain further mechanistic insights into processes regulated by sex hormones by analyzing relevant DEGs, i.e. genes whose differential expression was consistent with the predicted activation status in the three experimental groups (Fig. 4). Genes were separated into activators or inhibitors of cell death or cell differentiation. The dataset related to cell death included DEGs associated with the following functional categories: cell death and survival, cellular growth and proliferation, and tissue development. Notably, Pax9 and Sgpl1, which are known to regulate TEC survival and apoptosis3233, were among DEGs linked to inhibition of cell death in male TECs (Fig. 4a). Furthermore, many genes known to regulate survival of different epithelial cell types are present in that list, including Sgk1, Id1, Vdr, Bcl2l14, Dusp1, Bmx and Igfbp3 (mammary gland), Pgf, Irf5, Pla2g4a and Pmepa1 (intestine), and Hspa1a (ovary)343536. Finally, several members of key pathways regulating cell survival/death were among sexually dimorphic genes: heat shock proteins (Hspa1a, Hspa1b, Hspa2, Hspb1) and members of the p53 (Rnd3, Plk2, Sgpl1, Igfbp3, Pmepa1), Pi3k/Akt (Pik3r1, Pdgfc, Fn1) and Fas/caspases pathways (Mcl1, Hspa1b, Fn1, Bcl2l14, Lum).

f4: Relative expression of genes contributing to the inhibition of cell death and cell differentiation in male TECs.(a) Relative expression of genes that affect cell death in cTECs. (b) Relative expression of genes that affect cell differentiation in mTECs. Relative gene expression is depicted as a Z-score, calculated separately for cTECs and mTECs. Red corresponds to higher expression, whereas blue corresponds to lower expression.

Mentions:
We then sought to gain further mechanistic insights into processes regulated by sex hormones by analyzing relevant DEGs, i.e. genes whose differential expression was consistent with the predicted activation status in the three experimental groups (Fig. 4). Genes were separated into activators or inhibitors of cell death or cell differentiation. The dataset related to cell death included DEGs associated with the following functional categories: cell death and survival, cellular growth and proliferation, and tissue development. Notably, Pax9 and Sgpl1, which are known to regulate TEC survival and apoptosis3233, were among DEGs linked to inhibition of cell death in male TECs (Fig. 4a). Furthermore, many genes known to regulate survival of different epithelial cell types are present in that list, including Sgk1, Id1, Vdr, Bcl2l14, Dusp1, Bmx and Igfbp3 (mammary gland), Pgf, Irf5, Pla2g4a and Pmepa1 (intestine), and Hspa1a (ovary)343536. Finally, several members of key pathways regulating cell survival/death were among sexually dimorphic genes: heat shock proteins (Hspa1a, Hspa1b, Hspa2, Hspb1) and members of the p53 (Rnd3, Plk2, Sgpl1, Igfbp3, Pmepa1), Pi3k/Akt (Pik3r1, Pdgfc, Fn1) and Fas/caspases pathways (Mcl1, Hspa1b, Fn1, Bcl2l14, Lum).

Bottom Line:
These effects were exquisitely TEC-subset specific.Nevertheless, cTECs were more abundant in males than females.Accumulation of cTECs in males correlated with differential expression of genes regulating cell survival in cTECs and cell differentiation in mTECs.

ABSTRACTThe goal of our study was to evaluate at the systems-level, the effect of sex hormones on thymic epithelial cells (TECs). To this end, we sequenced the transcriptome of cortical and medullary TECs (cTECs and mTECs) from three groups of 6 month-old mice: males, females and males castrated at four weeks of age. In parallel, we analyzed variations in the size of TEC subsets in those three groups between 1 and 12 months of age. We report that sex hormones have pervasive effects on the transcriptome of TECs. These effects were exquisitely TEC-subset specific. Sexual dimorphism was particularly conspicuous in cTECs. Male cTECs displayed low proliferation rates that correlated with low expression of Foxn1 and its main targets. Furthermore, male cTECs expressed relatively low levels of genes instrumental in thymocyte expansion (e.g., Dll4) and positive selection (Psmb11 and Ctsl). Nevertheless, cTECs were more abundant in males than females. Accumulation of cTECs in males correlated with differential expression of genes regulating cell survival in cTECs and cell differentiation in mTECs. The sexual dimorphism of TECs highlighted here may be mechanistically linked to the well-recognized sex differences in susceptibility to infections and autoimmune diseases.